Hydrates of optionally substituted 2-(2-pyridinyl) methylthio-1H-benzimidazoles and process for the production thereof

ABSTRACT

The invention relates to crystals from optionally substituted  2 -( 2 -pyridinyl)methylthio- 1 H-benzimidazole hydrates and to a method for the production thereof.

[0001] The invention relates to crystals of optionally substituted2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates and to a process forthe production thereof.

[0002] It is known that 2-(2-pyridinyl)methylthio-1H-benzimidazolecompounds, such as for example pyrmetazole(5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1H-benzimidazole)are the final intermediate for the production of antiulceratives, inparticular omeprazole or lanzoprazole. Such an antiulcerative isproduced by converting the sulfide compound, such as for examplepyrmetazole, by oxidation into the corresponding sulfinyl compound, suchas for example omeprazole.

[0003] Substituted 2-(2-pyridinyl)methylthio-1H-benzimidazoles areconventionally produced under alkaline conditions in organic solvents byreaction of mercaptobenzimidazole compounds, such as for example5-methoxy-2-mercapto-benzimidazole, with reactive pyridine compounds,such as for example 2-chloromethyl-3,5-dimethyl-4-methoxypyridine.

[0004] EP 0 005 129 A describes the production of2-(2-pyridinyl)methylthio-1H-benzimidazole compounds by reactingsuitable mercaptobenzimidazole compounds with chloromethylpyridinecompounds. The reaction proceeds in an organic solvent, such as forexample ethanol, in the presence of a base, such as for example sodiumhydroxide. Once the reaction is complete, the resultant common salt isseparated, the solvent removed under a vacuum and the monohydrochlorideof the compound is caused to crystallise by means of concentratedhydrochloric acid in acetone and is purified. The yields achieved inthis process are barely satisfactory. Moreover, the hydrochloride mustbe converted back into the base before the oxidation reaction.

[0005] EP 0 074 341 A describes the production of2-(2-pyridinyl)-methylthio-1H-benzimidazole compounds by reactingsuitable mercaptobenzimidazole compounds with chloromethylpyridinecompounds in the presence of sodium hydroxide. Methanol is used as thesolvent. Once the reaction is complete and water has been added, the2-(2-pyridinyl)methylthio-1H-benzimidazole compound is purified byrepeated extraction with methylene chloride and recrystallisation fromacetonitrile. The solvents used in this process are hazardous to theenvironment. Moreover, due to the repeated extraction steps, the processis time-consuming.

[0006] EP 0 899 268 A2 describes inter alia the production of2-[2-(4-chloro-3,5-dimethylpyridyl)methylthio]-5-methoxy-1H-benzimidazoleby the reaction of suitable starting compounds in tetrahydrofuran and inthe presence of sodium hydroxide solution. Once the reaction is completeand water has been added, the stated compound is isolated by repeatedextraction with methylene chloride and evaporation of the solvent. Thecompound is obtained as a viscous oil. Disadvantageous features of thisprocess are the use of a solvent which is hazardous to the environmentand the time-consuming isolation by repeated extraction. Moreover, theproduct in the form of a viscous oil is more technically demanding tohandle than a crystalline compound.

[0007] The object of the present invention was accordingly to providethe optionally substituted 2-(2-pyridinyl)-methylthio-1H-benzimidazolesin a form which is stable and can be stored and is obtained bystraightforward processing steps in elevated yields and in high purity,wherein it is possible to use solvents which are more environmentallyfriendly and present a reduced hazard to health.

[0008] The object is achieved by the provision of crystals of optionallysubstituted 2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates of thestructural formula I,

[0009] in which

[0010] R¹, R² and R³, identical or different, denote

[0011] hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 fluoroalkyl orC1-C8 alkoxy,

[0012] R⁴ and R⁵, identical or different, denote

[0013] hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, CH₂-C3-C8 cycloalkyl,C1-C8 alkoxycarbonyl, C1-C8 alkoxy, C1-C8 fluoroalkoxy, CF₃, C2-C8fluoroalkyl or —C(O)O—C1-C8 alkyl and

[0014] R⁶, identical or different, denotes

[0015] hydrogen or C1-C2 alkyl and

[0016] x denotes 0.5-2.

[0017] R¹-R⁶ preferably have the following meaning

[0018] R¹, R² and R³, identical or different, denote hydrogen, C1-C3alkyl or C1-C3 alkoxy,

[0019] R⁴ and R⁵, identical or different, denote hydrogen, C1-C3 alkoxy,C1-C3 fluoroalkoxy and

[0020] R⁶, identical or different, denotes hydrogen.

[0021] Particularly preferred compounds are those

[0022] in which R¹ denotes a methyl group, R² a methoxy group, R³ amethyl group, R⁴ hydrogen, R⁵ a methoxy group in position 5 and R⁶hydrogen or

[0023] in which R¹ denotes hydrogen, R² and R³ in each case denote amethoxy group, R⁴ denotes hydrogen, R⁵ a difluoromethoxy group inposition 5 and R⁶ hydrogen.

[0024] The present invention also provides a process for the isolationof a compound according to formula I from a reaction medium, in whichthe compound is present as a free base, in elevated yields, wherein awater-miscible, organic solvent present in the reaction medium is atmost partially removed and water is added to the reaction medium at atemperature of below 40° C., preferably of 20-25° C., in quantities ofat least 55 wt. %, preferably at least 70 wt. %, particularly preferablyup to 75 wt. %, relative to the reaction medium, and the consequentlyformed hydrates are separated as crystals and optionally purified inconventional manner and dried. When removing the organic solvent, careshould be taken to ensure that its concentration does not fall below thesolubility limit for the compound of the formula I.

[0025] The compounds of the formula I are preferably to be separatedfrom a reaction medium which is obtained by reacting a thiol compound ofthe formula II

[0026] in which R⁴ and R⁵ have the above-stated meaning, with a reactivepyridine compound of the formula III,

[0027] in which R¹, R², R³ and R⁶ have the above-stated meaning, in awater-miscible, organic solvent in the presence of a base. Suitablebases for this reaction are preferably sodium and/or potassiumhydroxide. This reaction preferably proceeds with several hours'refluxing. The reaction may be performed continuously ordiscontinuously.

[0028] The compound of the formula I may be obtained from the reactionmedium, which contains the compound as a free base, by at most partialremoval of the water-miscible, organic solvent and by addition of waterin quantities of at least 55 wt. %, preferably at least 70 wt. %,particularly preferably up to 75 wt. %, relative to the reaction medium,at a temperature of below 40° C., preferably of 20-25° C. When removingthe organic solvent, care should be taken to ensure that itsconcentration does not fall below the solubility limit for the compoundof the formula I.

[0029] The sodium and/or potassium chloride arising from theneutralisation of the added base may be separated beforehand by suitablemeans, for example by filtration, or be dissolved by the addition ofwater on formation of the hydrate. The hydrates of the2-(2-pyridinyl)methylthio-1H-benzimidazoles may optionally be furtherpurified and dried.

[0030] Thiol compounds of the formula II may be purchased commercially.Reference is also made to EP 0 254 588, EP 0 005 129 and EP 0 074 341for a description of the synthesis thereof, the correspondingdescription hereby being introduced as part of the present disclosure.Reference is made to WO 98/50361 and WO 97/29103 for a description ofthe synthesis of the reactive pyridine compounds of the formula III, thecorresponding description hereby being introduced as part of the presentdisclosure.

[0031] The present invention also provides a process for the productionof a compound according to the formula I, in which the unhydratedcompound of the formula I is dissolved in a water-miscible, organicsolvent or solvent mixture and is caused to crystallise by addition ofwater in quantities of at least 55 wt. %, preferably at least 70 wt. %,particularly preferably up to 75 wt. %, relative to the reaction medium,at a temperature of below 40° C., preferably of 20-25° C., and theconsequently formed crystals of the compound according to the formula Iare separated, optionally purified and dried.

[0032] The water-miscible, organic solvents used in the above- statedreactions are preferably highly volatile solvents, such as aliphaticalcohols, aprotic solvents or ketones, particularly preferably methanol,ethanol, propanol, butanol, dimethylformamide, dimethyl sulfoxide,tetrahydrofuran or acetone, or mixtures of at least two of thesesolvents.

[0033] The present invention also provides a process for thepurification of crystals of a compound according to the formula I, inaccordance with which the hydrate to be purified is washed at least oncewith water and/or a solvent/water mixture, preferably an alcohol/watermixture and/or a ketone/water mixture, and is then dried under a vacuumat below the melting point of the hydrates.

[0034] The crystals according to the invention of the optionallysubstituted 2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates of theformula I are stable and can be stored. They are straightforward toproduce, isolate and purify and may be used directly for oxidation toyield the corresponding sulfinyl compounds, which are used as anantiulcerative. With the assistance of the process according to theinvention, it is possible to produce crystals of optionally substituted2-(2-pyridinyl)-methylthio-1H-benzimidazole hydrates of the formula I inelevated yields and in high purity, wherein it is possible to usesolvents which are more environmentally friendly and present a reducedhazard to health.

[0035] The following Examples illustrate the invention without limitingit thereto.

EXAMPLES Example 1

[0036] 0.05 mol of 2-mercapto-5-methoxybenzimidazole were added to asolution of 0.11 mol of sodium hydroxide in 90 ml of ethanol. 0.05 molof 2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine hydrochloride wereadded to the solution and the reaction mixture was refluxed for 14hours. 270 ml of water were then added at room temperature (25° C.),wherein the hydrates of5-methoxy-2-[3,5-dimethyl-4-methoxypyridinyl)-methylthio]-1H-benzimidazolecrystallised. The whitish crystalline product was separated, washed withwater and dried under a vacuum.

[0037] Yield: 95% relative to theoretical yield (15.6 g). The purity ofthe compound was determined by HPLC and was 99.7%.

Example 2

[0038] 0.1 mol of 2-mercapto-5-methoxybenzimidazole were added to asolution of 0.22 mol of sodium hydroxide in 250 ml of methanol. 0.1 molof 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride wereadded to the solution and the reaction mixture was refluxed for 16hours. 80 ml of solvent were then removed under a vacuum and 400 ml ofwater were then added at room temperature (25° C.), wherein the hydratesof5-methoxy-2-[3,5-dimethyl-4-methoxy-pyridinyl)methylthio]-1H-benzimidazolecrystallised. The whitish crystalline product was separated, washed withmethanol/water and dried under a vacuum.

[0039] Yield: 92.5% relative to theoretical yield (30.3 g). The purityof the compound was determined by HPLC and was 99.5%.

Example 3

[0040] 0.1 mol of pyrmetazole hydrochloride (the compound was producedaccording to details stated in Example 31 of EP 0 005 129) weredissolved in 60 ml of water, then 60 ml of ethanol were added, the pHvalue of the solution was adjusted to greater than pH 7 with a 5 Nsodium hydroxide solution and a further 120 ml of water were added atroom temperature (25° C.), wherein the hydrates of the pyrmetazolecrystallised. The whitish crystalline product was separated, washed withwater and dried under a vacuum.

[0041] Yield: 90.2% relative to theoretical yield (29.5 g). The purityof the compound was determined by HPLC and was 99.9%.

Example 4

[0042] Pyrmetazole, in the form of a solution in methylene chloride, wasfirst produced according to Example 26 of EP 0 899 268. Methylenechloride was removed under a vacuum from such a solution, whichcontained 0.1 mol of pyrmetazole. The residual oil was dissolved in 210ml of ethanol and caused to crystallise as the hydrate of pyrmetazole bythe addition of 630 ml of water. The whitish crystalline product wasseparated, washed with water and dried under a vacuum.

[0043] Yield: 96% relative to theoretical yield (31.5 g). The purity ofthe compound was determined by HPLC and was 99.8%.

1. Crystals of optionally substituted2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates of the followingstructural formula I

in which R¹, R² and R³, identical or different, denote hydrogen, a C1-C8alkyl, C3-C8 cycloalkyl, C2-C8 fluoroalkyl or C1-C8 alkoxy residue, R⁴and R⁵, identical or different, denote hydrogen, a C1-C8 alkyl, C3-C8cycloalkyl, CH₂—C3-C8 cycloalkyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxy,C1-C8 fluoroalkoxy, CF₃—, C2-C8 fluoroalkyl or C(O)O—C1-C8 alkyl residueand R⁶ denotes hydrogen or a C1-C2 alkyl residue and x means 0.5-2. 2.Crystals according to claim 1, in which R¹, R² and R³, identical ordifferent, denote hydrogen, a C1-C3 alkyl or C1-C3 alkoxy residue, R⁴and R⁵, identical or different, denote hydrogen, a C1-C3 alkoxy, C1-C3fluoroalkoxy residue and R⁶ denotes hydrogen and x means 0.5-2. 3.Crystals according to claim 1 or 2, in which R¹ denotes a methyl group,R² a methoxy group, R³ a methyl group, R⁴ hydrogen, R⁵ a methoxy groupin position 5 and R⁶ hydrogen and x means 0.5-2.
 4. Crystals accordingto claim 1 or 2, in which R¹ denotes hydrogen, R² and R³ in each casedenote a methoxy group, R⁴ denotes hydrogen, R⁵ a difluoromethoxy groupin position 5 and R⁶ hydrogen and x means 0.5-2.
 5. A process for theisolation of a compound according to one of claims 1-4 from a reactionmedium containing the free base, characterised in that a water-soluble,organic solvent present in the reaction medium is at most partiallyremoved, water is added to the reaction medium at a temperature of below40° C. water in quantities of at least 55 wt. %, relative to thereaction medium, and the hydrates formed are separated as crystals andoptionally purified in conventional manner.
 6. A process according toclaim 5, characterised in that water is added in quantities of at least70 wt. % relative to the reaction medium.
 7. A process according toclaim 5, characterised in that water is added in quantities of up to 75wt. % relative to the reaction medium.
 8. A process according to one ofclaims 5-7, characterised in that the water is added at a temperature of20-25° C.
 9. A process according to one of claims 5-8, characterised inthat an unhydrated compound of the formula I was obtained in thereaction medium by reacting a thiol-compound of the formula II

with a reactive pyridine compound of the formula III

in presence of at least one base, wherein the residues R¹-R⁶ have themeaning stated in one of claims 1-4.
 10. A process according to claim 9,characterised in that sodium and/or potassium hydroxide was used as thebase.
 11. A process according to one of claims 5-8, characterised inthat the unhydrated compound of the formula I was initially dissolved ina water-miscible, organic solvent.
 12. A process according to one ofclaims 5-11, characterised in that the water-miscible, organic solventis an aliphatic alcohol, preferably methanol, ethanol, propanol orbutanol, or an aprotic solvent, preferably dimethylformamide, dimethylsulfoxide, tetrahydrofuran, or a ketone, preferably acetone, or amixture of at least two these solvents.
 13. A process according to oneof claims 5-12, characterised in that the crystals are purified bywashing with water and/or a solvent/water mixture, preferably analcohol/water mixture and/or a ketone/water mixture.